The present invention is generally in the area of methods for making polysaccharides which include attached lipophilic groups, but which remain water-soluble.
Modified polysaccharides have been isolated from natural sources or synthesized chemically and their biological activities studied. Starches containing bound protein and lipid groups have been isolated from plant components such as seeds. See, e.g., Tharanathan et al., Starch, 42:247-251 (1990).
Fatty acid esters of polysaccharides have been produced by treatment of the polysaccharides with fatty acid chlorides or anhydrides or by ester exchange, and the alkyl ethers of polysaccharides have been produced by several methods (Methods in Carbohydrate Chemistry, vol. II (1963) Ed., R. L. Whistler and M. L. Wolfrom, Academic Press, New York; Section VI and V). However, most previous studies of this type have involved high degrees of derivatization with relatively short hydrocarbon chains, such as acetate esters or methyl ethers. Highly derivatized products of this type are generally water-insoluble. JP 60233560 to Fujirebio K.K. discloses a method of measuring lipase activity using as the enzyme substrate a water soluble fatty acid ester of a low molecular weight oligosaccharide such as dextran. JP 87209721 to Sugiyama Industrial Chemical Institute discloses the preparation of water soluble fatty acid esters of hydrolyzed starch for use as emulsifiers and detergents.
The synthesis of cyclodextrin derivatives, modified by the attachment of fatty acids or alcohols, which may be used as bile acid absorption agents, is described in DE 4 136 325 to Ahlers et al. PCT WO 95/12620 to Alpha-Beta Technology, Inc. discloses derivatized polysaccharide bile acid sequestrants for reducing cholesterol which include a hydrophobic, cationic ligand coupled to a polysaccharide substrate.
Acetylated mannans "acemannans" are long-chain polydispersed beta-1,4-linked mannan polymers interspersed with O-acetyl groups which are isolated from the Aloe vera leaf. Acemannans have been reported to have antitumor activity and to be useful as adjuvants. Harris et al., Mol. Biother. 3:207-213 (1991). Acetylated mannans also have been reported to be useful for regulating blood cholesterol levels; for reducing inflammation and infection; as an immunostimulant; and as an antiviral. U.S. Pat. Nos. 5,441,943 and 5,308,838 to Carpenter et al.; PCT WO 93/08810 to Carrington Lab, Inc.; and U.S. Pat. Nos. 5,118,673 and 5,106,616 to Carpenter et al. Acemannans also have been shown to induce human cytokines. Marshall et al., Abstract presented at the American Academy of Allergy and Immunology, Chicago, Ill., March, 1993.
It is an object of the invention to provide lipid-modified polysaccharides which are water-soluble, biocompatible and can be used in a variety of different biomedical applications. It is a further object of the invention to provide water soluble, lipid-modified forms of arabinogalactan which can be used in different applications, for example, to promote the formation of stable emulsions, to increase drug solubility, and to serve as adjuvants. It is another object of the invention to provide methods for making and using a range of such modified forms of arabinogalactan in different biomedical applications.